Cosmetic use of 1-Aroyl-N-(2-oxo-3-piperidinyl)-2-piperazine carboxamides and related compounds

ABSTRACT

Cosmetic compositions comprising 1-aroyl-N-(2-oxo-3-piperidinyl)-2-piperazine carboxamides and methods of using such compositions to impart anti-aging benefits to the skin are disclosed. The 1-aroyl-N-(2-oxo-3-piperidinyl)-2-piperazine carboxamides are believed to have modulatory activity against one or more biochemical pathways implicated in skin aging.

CROSS-REFERENCE TO A RELATED APPLICATION

The present application is a divisional application of parentapplication U.S. Ser. No. 12/645,622, filed Dec. 23, 2009, now U.S. Pat.No. 7,993,663, which is a continuation-in-part application of parentapplication U.S. Ser. No. 12/344,868, filed Dec. 29, 2008, now U.S. Pat.No. 7,994,175, which are incorporated herein by reference in itsentirety.

FIELD OF INVENTION

The present invention relates generally to compositions for topicalapplication to the skin which comprise1-aroyl-N-(2-oxo-3-piperidinyl)-2-piperazine carboxamides and the use ofsuch compositions to provide benefits to the skin.

BACKGROUND OF THE INVENTION

The desmogleins are a family of transmembrane proteins which play animportant role in cell adhesion, ensuring that cells within tissue arebound together. In skin, they are major components in desmosomes.Desmosomes are cell-cell adhesion complex between epithelial and certainother cell types. They provide mechanical integrity to keratinocytes bylinking to keratin intermediate filaments. Desmogleins form the gluethat attaches adjacent skin cells, keeping the skin intact. Desmoglein 1and 3 are both expressed in stratified squamous epithelia. Desmoglein 1is dominantly expressed in the differentiated upper layer of epidermis,and Desmoglein 3 is mostly found in basal and suprabasal layers. Thedifferential expression pattern of Desmogleins is important forregulating epidermal functions. Changes of Desmoglein 1 and 3 expressionpattern in animal models disrupts keratinocyte proliferation and barrierfunction of skin. An anticipated benefit for the stimulation ofDesmogleins would be an increase in anchoring and adhesion betweenkeratinocytes leading to firmer skin and fewer wrinkles.

Collagen is the body's major structural protein and is composed of threeprotein chains wound together in a tight triple helix. This uniquestructure gives collagen a greater tensile strength than steel.Approximately 33 percent of the protein in the body is collagen. Thisprotein supports tissues and organs and connects these structures tobones. In fact, bones are also composed of collagen combined withcertain minerals such as calcium and phosphorus. Collagen plays a keyrole in providing the structural scaffolding surrounding cells thathelps to support cell shape and differentiation, similar to how steelrods reinforce a concrete block. The mesh-like collagen network bindscells together and provides the supportive framework or environment inwhich cells develop and function, and tissues and bones heal.

Collagen is created by fibroblasts, which are specialized skin cellslocated in the dermis. Fibroblasts also produce other skin structuralproteins such as elastin (a protein which gives the skin its ability tosnap back) and glucosaminoglycans (GAGs). GAGs make up the groundsubstance that keeps the dermis hydrated. In order to signal or turn onthe production of skin structural proteins, fibroblast cells havespecially shaped receptors on their outside membranes that act asbinding sites to which signal molecules with a matching shape can fit.When the receptors are bound by the correct combination of signalmolecules (called fibroblast growth factors, or FGFs), the fibroblastbegins the production of collagen. The stimulation of collagen gives theskin its strength, durability, and smooth, plump appearance.

Dermatopontin is a protein component of the extracellular matrix whichis located primarily on the surface of the collagen fibers in the skin.Dermatopontin is believed to play important roles in cell-matrixinteractions and matrix assembly (collagen fibrillogenesis).Investigation of dermatopontin knockout mice confirm the involvement ofdermatopontin in skin elasticity and collagen accumulation, as theelastic modulus of skin was reported to be 57% lower and collagencontent was 40% lower in dermatopontin-null mice than in wild-type mice.Takeda et al., “Targeted disruption of dermatopontin causes abnormalcollagen fibrillogenesis,” J. Invest. Dermatol, 2002 September;119(3):678-83.

It is therefore an object of the invention to provide new compositionsand methods for stimulating collagen I, desmogleins, and/ordermatopontin production. It is a further object of the invention toimprove the overall appearance of skin, including treating, reversing,and/or preventing signs of aging, such as skin wrinkles, by stimulatingcollagen I, desmogleins, and/or dermatopontin production with cosmeticcompositions comprising effective amounts of1-aroyl-N-(2-oxo-3-piperidinyl)-2-piperazine carboxamides.

The foregoing discussion is presented solely to provide a betterunderstanding of nature of the problems confronting the art and shouldnot be construed in any way as an admission as to prior art nor shouldthe citation of any reference herein be construed as an admission thatsuch reference constitutes “prior art” to the instant application.

SUMMARY OF THE INVENTION

In accordance with the foregoing objectives and others, it hassurprisingly been found that1-aroyl-N-(2-oxo-3-piperidinyl)-2-piperazine carboxamides are potentstimulators of collagen I, desmogleins, and/or dermatopontin productionand thus are beneficial agents against various signs of intrinsic agingand photo-aging of skin.

In one aspect of the invention, cosmetic compositions are provided forimproving the aesthetic appearance of skin comprising, in a cosmeticallyacceptable vehicle, an effective amount of a collagen I, desmogleins,and/or dermatopontin enhancing1-aroyl-N-(2-oxo-3-piperidinyI)-2-piperazine carboxamide having thestructure of formula 1:

where R₁, R₂, R₃, R₄, R₅, R₆, and R₇ are independently hydrogen or agroup —R₉-R₁₀;

where R₉ represents, independently at each occurrence, a bond (i.e., R₉is absent) or one of the following: (i) an aliphatic C₁-C₂₀ hydrocarbonradical; (ii) a C₁-C₂₀ aromatic hydrocarbon radical; (iii) a C₁-C₂₀heteroaryl radical;

R₁₀ is selected independently at each occurrence from hydrogen; —F; —Cl;—Br; —I; —OH, —OR; —NH₂; —NHR; —N(R)₂; —N(R)₃ ⁺; —N(R)—OH; —N(→O)(R)₂;—O—N(R)₂; —N(R)—O—R; —N(R)—N(R)₂; —C═N—R; —N═C(R)₂; —C═N—N(R)₂;—C(═NR)—N(R)₂; —SH; —SR; —CN; —NC; —CHO; —CO₂H; —CO₂ ⁻; —CO₂R;—(C═O)—S—R; —O—(C═O)—H; —O—(C═O)—R; —S—(C═O)—R; —(C═O)—NH₂;—(C═O)—N(R)₂; —(C═O)—NHNH₂; —O—(C═O)—NHNH₂; —(C═S)—NH₂; —(C═S)—N(R)₂;—N(R)—CHO; —N(R)—(C═O)—R; —(C═NR)—O—R; —O—(C═NR)—R, —SCN; —NCS; —NSO;—SSR; —N(R)—C(═O)—N(R)₂; —N(R)—C(═S)—N(R)₂; —SO₂—R; —O—S(═O)₂—R;—S(═O)₂—OR; —N(R)—SO₂—R; —SO₂—N(R)₂; —O—SO₃ ⁻; —O—S(═O)₂—OR;—O—S(═O)—OR; —O—S(═O)—R; —S(═O)—OR; —S(═O)—R; —NO; —NO₂; —NO₃; —O—NO;—O—NO₂; —N₃; —N₂—R; —N(C₂H₄); —Si(—R)₃; —CF₃; —O—CF₃; —(C═O)—R; —PR₂;—O—P(═O)(OR)₂; —P(═O)(OR)₂; ═O; ═S; ═NR; an aliphatic C₁-C₂₀ hydrocarbonradical; a C₁-C₂₀ aromatic hydrocarbon radical; or a C₁-C₂₀ hacroarylradical;

where R is independently at each occurrence hydrogen or a saturated,partially saturated, or aromatic C₁-C₂₀ hydrocarbon radical, includinghalo and perhalo derivatives thereof;

and where any two adjacent groups R₁, R₂, R₃ R₄, and R₅ may, togetherwith the phenyl ring to which they are attached, form a five-membered orsix-membered aliphatic or aromatic ring, optionally substituted with oneor more groups R₁₀ and optionally including one or more heteroatomsselected from O, N, S in the ring.

Also provided is a method of treating one or more signs of skin agingcomprising topically applying to skin in need thereof a1-aroyl-N-(2-oxo-3-piperidinyl)-2-piperazine carboxamide according toformula I in an amount effective to enhance collagen I, desmogleins,and/or dermatopontin.

In another aspect of the invention, a method of treating, ameliorating,and/or preventing fine lines or wrinkles or sagging in human skin isprovided, comprising topically applying to skin in need thereof,including applying directly to a wrinkle or fine line, a compositioncomprising a 1-aroyl-N-(2-oxo-3-piperidinyI)-2-piperazine carboxamideaccording to formula I in an amount effective to enhance collagen I,desmogleins, and/or dermatopontin.

These and other aspects of the present invention will be betterunderstood by reference to the following detailed description andaccompanying figures.

DETAILED DESCRIPTION

All terms used herein are intended to have their ordinary meaning unlessotherwise provided.

The present invention provides compositions for topical applicationwhich comprise and effective amount of1-aroyl-N-(2-oxo-3-piperidinyl)-2-piperazine carboxamides or a relatedcompound to treat, reverse, ameliorate and/or prevent signs of skinaging. Such signs of skin aging include without limitation, thefollowing:

-   -   (a) treatment, reduction, and/or prevention of fine lines or        wrinkles,    -   (b) reduction of skin pore size,    -   (c) improvement in skin thickness, plumpness, and/or tautness;    -   (d) improvement in skin suppleness and/or softness;    -   (e) improvement in skin tone, radiance, and/or clarity;    -   (f) improvement in procollagen and/or collagen production;    -   (g) improvement in maintenance and remodeling of elastin;    -   (h) improvement in skin texture and/or promotion of        retexturization;    -   (i) improvement in skin barrier repair and/or function;    -   (j) improvement in appearance of skin contours;    -   (k) restoration of skin luster and/or brightness;    -   (l) replenishment of essential nutrients and/or constituents in        the skin;    -   (m) decreased by aging and/or menopause;    -   (n) improvement in skin moisturization; and/or    -   (o) increase in skin elasticity and/or resiliency;    -   (p) treatment, reduction, and/or prevention of skin sagging.

In practice, the compositions of the invention are applied to skin inneed of treatment. That is, skin which suffers from a deficiency or lossin any of the foregoing attributes or which would otherwise benefit fromimprovement in any of the foregoing skin attributes.

In certain preferred embodiments the compositions and methods of theinvention are directed to the prevention, treatment, and/or ameliorationof fine lines and/or wrinkles in the skin. In this case, thecompositions are applied to skin in need of treatment, by which is meantskin having wrinkles and/or fine lines. Preferably, the compositions areapplied directly to the fine lines and/or wrinkles. The compositions andmethods are suitable for treating fine lines and/or wrinkles on anysurface of the skin, including without limitation, the skin of the face,neck, and/or hands.

The cosmetic compositions for treating a skin condition associated withloss of collagen and/or elastin fiber comprise, in a cosmeticallyacceptable vehicle, an amount of a1-aroyl-N-(2-oxo-3-piperidinyl)-2-piperazinc carboxamides effective toenhance collagen I, desmogleins, and/or dermatopontin. These collagen I,desmogleins, and/or dermatopontin enhancing agents may have thestructure of formula (1):

In formula (I), R₁, R₂, R₃, R₄, R₅, R₆, and R₇ are independentlyhydrogen or a group —R₉-R₁₀. In one embodiment, at least one of thesubstituents on the phenyl ring, R₁, R₂, R₃, R₄, and R₅, will be a group—R₉-R₁₀ while in other embodiments R₃ will be a group —R₉-R₁₀ and R₁,R₂, R₄, and R₅ are hydrogen, such that the phenyl ring is substituted inthe para position, or R₁ will be a group —R₉-R₁₀ and R₂, R₂, R₄, and R₅are hydrogen, such that the phenyl ring is substituted in the orthoposition, or R₂ will be a group —R₉-R₁₀ and R₁, R₃, R₄, and R₅ arehydrogen, such that the phenyl ring is substituted in the meta position.

In one embodiment, R₇ and/or R₈ represent hydrogen. In otherembodiments, R₇ and R₈ independently represent hydrogen or a group—R₉-R₁₀, where R₉ is typically absent and where R₁₀ is preferably alower alkyl group (e.g., methyl, ethyl, propyl, butyl, etc.), typicallymethyl. R₆ may be hydrogen, but will usually be a group —R₉-R₁₀. In someembodiments according to formula (I), at least one of R₆, R₇ and R₈represent a group —R₉-R₁₀ while in other embodiments R₆ a group —R₉-R₁₀while R₇ and R₈ independently represent hydrogen or lower alkyl group(e.g., methyl, ethyl, propyl, butyl, etc.), typically methyl.

In the compounds of formula (I), R₉ represents, independently at eachoccurrence, a bond (i.e., R₉ is absent) or one of the following: (i) analiphatic C₁-C₂₀ hydrocarbon radical; including an aliphatic C₁-C₁₂hydrocarbon radical, an aliphatic C₁-C₈ hydrocarbon radical, or analiphatic C₁-C₆ hydrocarbon radical, as exemplified by substituted orunsubstituted branched, straight chain or cyclic, alkyl, alkenyl (e.g.,vinyl, allyl, etc.), and alkynyl moieties; (ii) a C₆-C₂₀ aromatichydrocarbon radical, including a C₆-C₁₂ aromatic hydrocarbon radical, aC₆-C₁₀ aromatic hydrocarbon radical, or a C₆ aromatic hydrocarbonradical, as exemplified by substituted or unsubstituted aryl (e.g.,phenyl), alkyl-aryl (e.g., benzyl), aryl-alkyl, and the like; (iii) aC₁-C₂₀ heteroaryl radical including one or more heteroatoms selectedfrom O, N, and S in the ring; including C₁-C₁₂ heteroaromatic radicals,C₁-C₈ heteroaromatic radicals, and C₁-C₆ heteroaromatic radicals, asexemplified by heteroaryl, alkyl-heteroaryl, heteroaryl-alkyl and thelike.

In some embodiments, R₉ is absent at one or more occurrences, such thatit represents a bond connecting R₁₀ directly to the phenyl group ornitrogen atoms of the 1-aroyl-N-(2-oxo-3-piperidinyl)-2-piperazinecarboxamide. In other embodiments, R₉ represents, independently at eachoccurrence, a bond (i.e., R₉ is absent) or a group selected from linearalkyl moieties of the form —(CH₂)_(a)— where “a” is an integer from 1 to6, including, for example, —CH₂— (methylene), —CH₂CH₂—, —CH₂CH₂CH₂—, or—CH₂CH₂CH₂CH₂—; —C(CH₃)₂—, —CH(CH₃)CH₂—, —C(CH₃)₂CH₂—, —C₆H₄—,—CH₂—C₆H₄—; linear alkoxy moieties of the general form —(CH₂)_(a)O— or—O(CH₂)_(a)— where “a” is an integer from 1 to 6, including for example,—CH₂O— or —OCH₂—, —CH₂CH₂O— or —OCH₂CH₂—, —CH₂CH₂CH₂O— or —OCH₂CH₂CH₂—;—O(CH₂)_(a)O— where “a” is as defined above; or a moiety of the form—(CH₂)_(b)O(CH₂)_(c)—, —(CH₂)_(b)S(CH₂)_(c)—, or —(CH₂)_(b)NR(CH₂)_(c)—wherein “b” and “c” are independently an integer from 0 (zero) to 6 andR is as defined above. In some embodiments, R₉ represents a bond, acarbonyl group —(C═O)—, or a methylene group —CH₂—.

R₁₀ is selected independently at each occurrence from hydrogen; —F; —Cl;—Br; —I; —OH, —OR; —NH₂; —NHR; —N(R)₂; —N(R)₃ ⁺; —N(R)—OH; —N(→O)(R)₂;—O—N(R)₂; —N(R)—O—R; —N(R)—N(R)₂; —C═N—R; —N═C(R)₂; —C═N—N(R)₂;—C(═NR)—N(R)₂; —SH; —SR; —CN; —NC; —CHO; —CO₂H; —CO₂ ⁻; —CO₂R;—(C═O)—S—R; —O—(C═O)—H; —O—(C═O)—R; —S—(C═O)—R; —(C═O)—NH₂;—(C═O)—N(R)₂; —(C═O)—NHNH₂; —O—(C═O)—NHNH₂; —(C═S)—NH₂; —(C═S)—N(R)₂;—N(R)—CHO; —N(R)—(C═O)—R; —(C═NR)—O—R; —O—(C═NR)—R, —SCN; —NCS; —NSO;—SSR; —N(R)—C(═O)—N(R)₂; —N(R)—C(═S)—N(R)₂; —SO₂—R; —O—S(═O)₂—R;—S(═O)₂—OR; —N(R)—SO₂—R; —SO₂—N(R)₂; —O—SO₃ ⁻; —O—S(═O)₂—OR;—O—S(═O)—OR; —O—S(═O)—R; —S(═O)—OR; —S(═O)—R; —NO; —NO₂; —NO₃; —O—NO;—O—NO₂; —N₃; —N—R₂; —N(C₂H₄); —Si(—R)₃; —CF₃; —O—CF₃; —(C═O)—R; —PR₂;——O—P(═O)(OR)₂; —P(═O)(OR)₂; ═O; ═S; ═NR; aliphatic C₁-C₂₀ hydrocabonradicals; including aliphatic C₁-C₁₂ hydrocarbon radicals, aliphaticC₁-C₈ hydrocarbon radicals, or an aliphatic C₁-C₆ hydrocarbon radicals,as exemplified by substituted or unsubstituted branched, straight chainor cyclic, alkyl, alkenyl (e.g., vinyl, allyl, etc.), and alkynylmoieties; C₆-C₂₀ aromatic hydrocarbon radicals, including C₆-C₁₂aromatic hydrocarbon radicals, C₆-C₁₀ aromatic hydrocarbon radicals, orC₆ aromatic hydrocarbon radicals, as exemplified by substituted orunsubstituted aryl (e.g., phenyl), alkyl-aryl (e.g., benzyl),aryl-alkyl, and the like; or C₁-C₂₀ heteroaryl radicals including one ormore heteroatoms selected from O, N, and S in the ring; including C₁-C₁₂heteroaromatic radicals, C₁-C₈ heteroaromatic radicals, and C₁-C₆heteroaromatic radicals, as exemplified by heteroaryl, alkyl-heteroaryl,heteroaryl-alkyl and the like.

R is independently at each occurrence hydrogen or a saturated, partiallysaturated, or aromatic C₁-C₂₀ hydrocarbon radical, C₁-C₁₂ hydrocarbonradical, C₁-C₈ hydrocarbon radical, or C₁-C₆ hydrocarbon radical, eachoptionally including one or more heteroatoms, such as oxygen, sulfur,and nitrogen atoms. Preferably, R is selected from substituted orunsubstituted branched, straight chain or cyclic C₁-C₂₀ alkyl, alkenyl,alkynyl, aryl, benzyl, heteroaryl, alkyl-aryl, aryl-alkyl,alkyl-heteroaryl, heteroaryl-alkyl, heteroaryl-aryl, bicyclic alkyl,aryl, or heteroaryl radicals, and combinations thereof; wherein theforegoing radicals may be substituted with any moiety, including, forexample, hydroxyl, amino, cyano, halogen, oxo, carboxy, carboxamide,nitro, azo, alkoxyl, alkyl, alkylimino, alkylamino, dialkylamino,thioalkoxy and combinations thereof. R may be, for example,independently at each occurrence, hydrogen, methyl, ethyl, propyl,butyl, pentyl, hexyl, phenyl, benzyl, or the like, including halo andperhalo derivatives thereof. In some embodiments, R will be hydrogen,methyl, ethyl, phenyl or benzyl, most typically methyl or phenyl.

In formula (I), it will be further understood that any two adjacentgroups R₁, R₂, R₃ R₄, and R₅ may, together with the phenyl ring to whichthey are attached, form a five-membered or six-membered aliphatic oraromatic ring, optionally substituted with one or more groups R₁₀ andoptionally including one or more heteroatoms selected from O, N, S inthe ring. In some embodiments, any two adjacent groups R₁, R₂, R₃ R₄,and R₅ may, together with the phenyl ring to which they are attached,form a heterocyclic ring fused to the phenyl ring, which heterocyclicring may be aromatic, partially saturated, or fully saturated,including, without limitation, four membered rings (azetidine, oxetane,thietane, etc.), five membered rings (pyrrole, pyrrolidine, furan,oxolane, thiophene, thiolane, pyrazole, imidazole, imidazolidine,oxazole, isoxazole, oxazolidine, thiazole, isothiazole, thiazolidine,dioxolane, dithiolane, 1,2,3-triazole, 1,2,4-triazole, dithiazole,tetrazole, etc.), and six membered rings (piperidine, pyridine,tetrahydropyran, pyran, thiane, thiine, piperazine, diazine, oxazine,thiazine, dithiane, dioxane, dioxin, morpholine, quinoline, etc.).

Further, any nitrogen atom may be optionally oxidized to the N-oxide orcan be quarternized, for example with loweralkyl halides, such asmethyl, ethyl, propyl, and butyl chloride, bromides, and iodides;dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates,long chain halides such as decyl, lauryl, myristyl and stearylchlorides, bromides and iodides, aralkyl halides such as benzyl andphenethyl bromides, to name a few.

In one embodiment according to formula (I), R₁, R₂, R₄, R₅, R₇ and R₈represent hydrogen as shown in formula (Ia).

where R₃ and R₆ are independently hydrogen or a group —R₉-R₁₀ as definedabove. In some embodiments, R₃ will be a group —OR (i.e., R₉ is absentand R₁₀ is —OR), where R represents hydrogen, methyl, ethyl, propyl,iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl,phenyl, or benzyl as well as halo and perhalo derivatives thereof, forexample trifluoromethyl. In one embodiment, R₃ will be a group —OR whereR represents methyl to define a methoxy group in the para position ofthe phenyl ring as shown in formula (Ib):

where R₆ is hydrogen or a group —R₉-R₁₀ as defined above. Preferably, R₆is hydrogen or a group —R₉-R₁₀ where R₉ is absent and where R₁₀ isselected from (i) acyl groups of the form —(C═O)—R, where R is asdefined above, but is typically selected from methyl, ethyl, propyl,butyl, pentyl, hexyl, phenyl, toluyl, or benzyl, (preferably phenyl);and (ii) —SO₂—R groups where R is as defined above, but is typicallyselected from methyl, ethyl, propyl, butyl, pentyl, hexyl, phenyl,toluyl, or benzyl, (preferably methyl).1-aroyl-N-(2-oxo-3-piperidinyl)-2-piperazine carboxamide compoundsaccording to formula (Ib) where R₆ is —(C═O)—C₆H₅ (i.e. benzoyl) or—SO₂—CH₃ are commercially available from Analyticon GmbH (Berlin,Germany).

In a particular embodiment, a cosmetic composition comprises, in acosmetically acceptable vehicle, preferably a water-in-oil oroil-in-water emulsion, from about 0.0001% to about 90% by weight of a1-aroyl-N-(2-oxo-3-piperidinyl)-2-piperazine carboxamide having thestructure:

or a cosmetically acceptable salt thereof.

In another particular embodiment, a cosmetic composition comprises, in acosmetically acceptable vehicle, preferably a water-in-oil oroil-in-water emulsion, from about 0.0001% to about 90% by weight of a1-aroyl-N-(2-oxo-3-piperidinyl)-2-piperazine carboxamide having thestructure:

or a cosmetically acceptable salt thereof.

The compounds of formula (1) comprise one stereocenter on the piperazinering and one sterocenter on the lactam ring. Each of these sterocentersmay be in the R or S configuration. Accordingly, the compounds accordingto formula (i) may exist as a pure (R,R), (R,S), (S,R), or (S,S)diastereomer with respect to these two chiral centers or may comprise amixture of two or more diastereomer. By “pure” is meant that theparticular diastereomer comprises at least 95% by weight of the totalweight of formula (I) compound, and preferably at least 98% or at least99% by weight.

The invention embraces the use of cosmetically or pharmaceuticallyacceptable (e.g., non-toxic and/or non-irritating) salts. Examples ofthe salts of the compounds in the present invention include salts withalkali metals such as sodium and potassium; salts with alkaline-earthmetals such as calcium and magnesium; salts with amines such asmonoethanolamine; salts with inorganic acids such as hydrochloric acidand sulfuric acid; and salts with organic acids such as citric acid andacetic acid. Special mention may be made of hydrochloride salts.

The cosmetic compositions according to the invention can be formulatedin a variety of forms for topical application and will comprise fromabout 0.0001% to about 90% by weight of one or more compounds accordingto formula (I), and preferably will comprise from about 0.001% to about25% by weight, and more preferably from about 0.01% to about 10% byweight. The compositions will comprise and effective amount of the1-aroyl-N-(2-oxo-3-piperidinyl)-2-piperazine carboxamide compoundsaccording to formula (I), by which is meant an amount sufficient toenhance collagen I, desmogleins, and/or dermatopontin in given area ofskin when topically applied thereto.

The composition may be formulated in a variety of product forms, suchas, for example, a lotion, cream, serum, spray, aerosol, cake, ointment,essence, gel, paste, patch, pencil, towelette, mask, stick, foam,elixir, concentrate, and the like, particularly for topicaladministration. Preferably the composition is formulated as a lotion,cream, ointment, or gel.

The compositions can include a cosmetically acceptable vehicle. Suchvehicles may take the form of any known in the art suitable forapplication to skin and may include water; vegetable oils; mineral oils;esters such as octal palmitate, isopropyl myristate and isopropylpalmitate; ethers such as dicapryl ether and dimethyl isosorbide;alcohols such as ethanol and isopropanol; fatty alcohols such as cetylalcohol, cetearyl alcohol, stearyl alcohol and biphenyl alcohol;isoparaffins such as isooctane, isododecane and is hexadecane; siliconeoils such as cyclomethicone, dimethicone, dimethicone cross-polymer,polysiloxanes and their derivatives, preferably organomodifiedderivatives; hydrocarbon oils such as mineral oil, petrolatum,isoeicosane and polyisobutene; polyols such as propylene glycol,glycerin, butylene glycol, pentylene glycol and hexylene glycol; waxessuch as beeswax and botanical waxes; or any combinations or mixtures ofthe foregoing.

The vehicle may comprise an aqueous phase, an oil phase, an alcohol, asilicone phase or mixtures thereof. The cosmetically acceptable vehiclemay also comprise an emulsion. Non-limiting examples of suitableemulsions include water-in-oil emulsions, oil-in-water emulsions,silicone-in-water emulsions, water-in-silicone emulsions, wax-in-wateremulsions, water-oil-water triple emulsions or the like having theappearance of a cream, gel or microemulsions. The emulsion may includean emulsifier, such as a nonionic, anionic or amphoteric surfactant.

The oil phase of the emulsion preferably has one or more organiccompounds, including emollients; humectants (such as propylene glycoland glycerin); other water-dispersible or water-soluble componentsincluding thickeners such as veegum or hydroxyalkyl cellulose; gellingagents, such as high MW polyacrylic acid, i.e. CARBOPOL 934; andmixtures thereof. The emulsion may have one or more emulsifiers capableof emulsifying the various components present in the composition.

The compounds suitable for use in the oil phase include withoutlimitation, vegetable oils; esters such as octyl palmitate, isopropylmyristate and isopropyl palmitate; ethers such as dicapryl ether; fattyalcohols such as cetyl alcohol, stearyl alcohol and behenyl alcohol;isoparaffins such as isooctane, isododecane and isohexadecane; siliconeoils such as dimethicones, cyclic silicones, and polysiloxanes;hydrocarbon oils such as mineral oil, petrolatum, isoeicosane andpolyisobutene; natural or synthetic waxes; and the like. Suitablehydrophobic hydrocarbon oils may be saturated or unsaturated, have analiphatic character and be straight or branched chained or containalicyclic or aromatic rings. The oil-containing phase may be composed ofa singular oil or mixtures of different oils.

Hydrocarbon oils include those having 6-20 carbon atoms, more preferably10-16 carbon atoms. Representative hydrocarbons include decane,dodecane, tetradecane, tridecane, and C₈₋₂₀ isoparaffins. Paraffinichydrocarbons are available from Exxon under the ISOPARS trademark, andfrom the Permethyl Corporation. In addition, C₈₋₂₀ paraffinichydrocarbons such as C12 isoparaffin (isododecane) manufactured by thePermethyl Corporation having the tradename Permethyl 99ATM are alsocontemplated to be suitable. Various commercially available C₁₆isoparaffins, such as isohexadecane (having the tradename Permethyl®)are also suitable. Examples of preferred volatile hydrocarbons includepolydecanes such as isododecane and isodecane, including for example,Permethyl-99A (Presperse Inc.) and the C₇-C₈ through C₁₂-C₁₅isoparaffins such as the Isopar Series available from Exxon Chemicals. Arepresentative hydrocarbon solvent is isododecane.

The oil phase may comprise one or more waxes, including for example,rice bran wax, carnauba wax, ouricurry wax, candelilla wax, montanwaxes, sugar cane waxes, ozokerite, polyethylene waxes, Fischer-Tropschwaxes, beeswax, microcrystaline wax, silicone waxes, fluorinated waxes,and any combination thereof.

Non-limiting emulsifiers included emulsifying waxes, emulsifyingpolyhydric alcohols, polyether polyols, polyethers, mono- or di-ester ofpolyols, ethylene glycol mono-stearates, glycerin mono-stearates,glycerin di-stearates, silicone-containing emulsifiers, soya sterols,fatty alcohols such as cetyl alcohol, fatty acids such as stcaric acid,fatty acid salts, and mixtures thereof. The preferred emulsifiersinclude soya sterol, cetyl alcohol, stearic acid, emulsifying wax, andmixtures thereof. Other specific emulsifiers that can be used in thecomposition of the present invention include, but are not limited to,one or more of the following: sorbitan esters;polyglyceryl-3-diisostearate; sorbitan monostearate, sorbitantristearate, sorbitan sesquioleate, sorbitan monooleate; glycerol esterssuch as glycerol monostearate and glycerol monooleate; polyoxyethylenephenols such as polyoxyethylene octyl phenol and polyoxyethylene nonylphenol; polyoxyethylene ethers such as polyoxyethylene cetyl ether andpolyoxyethylene stearyl ether; polyoxyethylene glycol esters;polyoxyethylene sorbitan esters; dimethicone copolyols; polyglycerylesters such as polyglyceryl-3-diisostearate; glyceryl laurate;Steareth-2, Steareth-10, and Steareth-20, to name a few. Additionalemulsifiers are provided in the INCI Ingredient Dictionary and Handbook11th Edition 2006, the disclosure of which is hereby incorporated byreference.

These emulsifiers typically will be present in the composition in anamount from about 0.001% to about 10% by weight, in particular in anamount from about 0.01% to about 5% by weight, and more preferably,below 1% by weight.

The oil phase may comprise one or more volatile and/or non-volatilesilicone oils. Volatile silicones include cyclic and linear volatiledimethylsiloxane silicones. In one embodiment, the volatile siliconesmay include cyclodimethicones, including tetramer (D4), pentamer (D5),and hexamer (D6) cyclomethicones, or mixtures thereof. Particularmention may be made of the volatile cyclomethicone-hexamethylcyclotrisiloxane, octamethyl-cyclotetrasiloxane, anddecamethyl-cyclopentasiloxane. Suitable dimethicones are available fromDow Corning under the name Dow Corning 200® Fluid and have viscositiesranging from 0.65 to 600,000 centistokes or higher. Suitable non-polar,volatile liquid silicone oils are disclosed in U.S. Pat. No. 4,781,917,herein incorporated by reference in its entirety. Additional volatilesilicones materials are described in Todd et al., “Volatile SiliconeFluids for Cosmetics”, Cosmetics and Toiletries, 91:27-32 (1976), hereinincorporated by reference in its entirety. Linear volatile siliconesgenerally have a viscosity of less than about 5 centistokes at 25° C.,whereas the cyclic silicones have viscosities of less than about 10centistokes at 25° C. Examples of volatile silicones of varyingviscosities include Dow Corning 200, Dow Coming 244, Dow Corning 245,Dow Corning 344, and Dow Corning 345, (Dow Corning Corp.); SF-1204 andSF-1202 Silicone Fluids (G.E. Silicones), GE 7207 and 7158 (GeneralElectric Co.); and SWS-03314 (SWS Silicones Corp.). Linear, volatilesilicones include low molecular weight polydimethylsiloxane compoundssuch as hexamethyldisiloxane, octamethyltrisiloxane,decamethyltetrasiloxane, and dodecamethylpentasiloxane, to name a few.

Non-volatile silicone oils will typically comprise polyalkylsiloxanes,polyarylsiloxanes, polyalkylarylsiloxanes, or mixtures thereof.Polydimethylsiloxanes are preferred non-volatile silicone oils. Thenon-volatile silicone oils will typically have a viscosity from about 10to about 60,000 centistokes at 25° C., preferably between about 10 andabout 10,000 centistokes, and more preferred still between about 10 andabout 500 centistokes; and a boiling point greater than 250° C. atatmospheric pressure. Non limiting examples include dimethylpolysiloxane (dimethicone), phenyl trimethicone, anddiphenyldimethicone. The volatile and non-volatile silicone oils mayoptionally be substituted will various functional groups such as alkyl,aryl, amine groups, vinyl, hydroxyl, haloalkyl groups, alkylaryl groups,and acrylate groups, to name a few.

The water-in-silicone emulsion may be emulsified with a nonionicsurfactant (emulsifier) such as, for example,polydiorganosiloxane-polyoxyalkylene block copolymers, including thosedescribed in U.S. Pat. No. 4,122,029, the disclosure of which is herebyincorporated by reference. These emulsifiers generally comprise apolydiorganosiloxane backbone, typically polydimethylsiloxane, havingside chains comprising -(EO)m- and/or -(PO)n-groups, where EO isethyleneoxy and PO is 1,2-propyleneoxy, the side chains being typicallycapped or terminated with hydrogen or lower alkyl groups (e.g., C₁₋₆,typically C₁₋₃). Other suitable water-in-silicone emulsifiers aredisclosed in U.S. Pat. No. 6,685,952, the disclosure of which is herebyincorporated by reference herein. Commercially availablewater-in-silicone emulsifiers include those available from Dow Corningunder the trade designations 3225C and 5225C FORMULATION AID; SILICONESF-1528 available from General Electric; ABIL EM 90 and EM 97, availablefrom Goldschmidt Chemical Corporation (Hopewell, Va.); and the SILWETseries of emulsifiers sold by OSI Specialties (Danbury, Conn.).

Examples of water-in-silicone emulsifiers include, but arc not limitedto, dimethicone PEG 10/15 crosspolymer, dimethicone copolyol, cetyldimethicone copolyol, PEG-15 lauryl dimethicone crosspolymer,laurylmethicone crosspolymer, cyclomethicone and dimethicone copolyol,dimethicone copolyol (and) caprylic/capric triglycerides, polyglyceryl-4isostearate (and) cetyl dimethicone copolyol (and) hexyl laurate, anddimethicone copolyol (and) cyclopentasiloxane. Preferred examples ofwater-in-silicone emulsifiers include, without limitation, PEG/PPG-18/18dimethicone (trade name 5225C, Dow Corning), PEG/PPG-19/19 dimethicone(trade name BY25-337, Dow Corning), Cetyl PEG/PPG-10/1 dimethicone(trade name Abil EM-90, Goldschmidt Chemical Corporation), PEG-12dimethicone (trade name SF 1288, General Electric), lauryl PEG/PPG-18/18methicone (trade name 5200 FORMULATION AID, Dow Corning), PEG-12dimethicone crosspolymer (trade name 9010 and 9011 silicone elastomerblend, Dow Corning), PEG-10 dimethicone crosspolymer (trade name KSG-20,Shin-Etsu), and dimethicone PEG-10/15 crosspolymer (trade name KSG-210,Shin-Etsu).

The water-in-silicone emulsifiers typically will be present in thecomposition in an amount from about 0.001% to about 10% by weight, inparticular in an amount from about 0.01% to about 5% by weight, and morepreferably, below 1% by weight.

The aqueous phase of the emulsion may include one or more additionalsolvents, including lower alcohols, such as ethanol, isopropanol, andthe like. The volatile solvent may also be a cosmetically acceptableester such as butyl acetate or ethyl acetate; ketones such as acetone orethyl methyl ketone; or the like.

The oil-containing phase will typically comprise from about 10% to about99%, preferably from about 20% to about 85%, and more preferably fromabout 30% to about 70% by weight, based on the total weight of theemulsion, and the aqueous phase will typically comprise from about 1% toabout 90%, preferably from about 5% to about 70%, and more preferablyfrom about 20% to about 60% by weight of the total emulsion. The aqueousphase will typically comprise from about 25% to about 100%, moretypically from about 50% to about 95% by weight water.

The compositions may include liposomes. The liposomes may comprise otheradditives or substances and/or may be modified to more specificallyreach or remain at a site following administration.

The composition may optionally comprise other cosmetic actives andexcipients, obvious to those skilled in the art including, but notlimited to, fillers, emulsifying agents, antioxidants, surfactants, filmformers, chelating agents, gelling agents, thickeners, emollients,humectants, moisturizers, vitamins, minerals, viscosity and/or rheologymodifiers, sunscreens, keratolytics, retinoids, hormonal compounds,alpha-hydroxy acids, alpha-keto acids, anti-mycobacterial agents,antifungal agents, antimicrobials, antivirals, analgesics, lipidiccompounds, anti-allergenic agents, H1 or H2 antihistamines,anti-inflammatory agents, anti-irritants, antineoplastics, immune systemboosting agents, immune system suppressing agents, anti-acne agents,anesthetics, antiseptics, insect repellents, skin cooling compounds,skin protectants, skin penetration enhancers, exfollients, lubricants,fragrances, colorants, depigmenting agents, hypopigmenting agents,preservatives, stabilizers, pharmaceutical agents, photostabilizingagents, sunscreens, and mixtures thereof. In addition to the foregoing,the cosmetic compositions of the invention may contain any othercompound for the treatment of skin disorders.

Colorants may include, for example, organic and inorganic pigments andpearlescent agents. Suitable inorganic pigments include, but are notlimited to, titanium oxide, zirconium oxide and cerium oxide, as well aszinc oxide, iron oxide, chromium oxide and ferric blue. Suitable organicpigments include barium, strontium, calcium, and aluminium lakes andcarbon black. Suitable pearlescent agents include mica coated withtitanium oxide, with iron oxide, or with natural pigment.

Various fillers and additional components may be added. Fillers arenormally present in an amount of about 0 weight % to about 20 weight %,based on the total weight of the composition, preferably about 0.1weight % to about 10 weight %. Suitable fillers include withoutlimitation silica, treated silica, talc, zinc stearate, mica, kaolin,Nylon powders such as Orgasol™, polyethylene powder, Teflon™, starch,boron nitride, copolymer microspheres such as Expancel™ (NobelIndustries), Polytrap™ (Dow Corning) and silicone resin microbeads(Tospearl™ from Toshiba), and the like.

In one embodiment of the invention, the compositions may includeadditional skin actives such as, but are not limited to, botanicals,keratolytic agents, desquamating agents, keratinocyte proliferationenhancers, collagenase inhibitors, elastase inhibitors, depigmentingagents, anti-inflammatory agents, steroids, anti-acne agents,antioxidants, salicylic acid or salicylates, thiodipropionic acid oresters thereof, and advanced glycation end-product (AGE) inhibitors.

In a specific embodiment, the composition may comprise at least oneadditional botanical, such as, for example, a botanical extract, anessential oil, or the plant itself. Suitable botanicals include, withoutlimitation, extracts from Abies pindrow, Acacia catechu, Amorphophalluscampanulatus, Anogeissus latifolia, Asmunda japonica, Azadirachtaindica, Butea frondosa, Butea monosperma, Cedrus deodara, Derrisscandens Benth., Emblica officinalis, Ficus benghalensis, Glycyrrhizaglabra, Harungana madagascariensis, Humulus scandens, Ilex purpureaHassk, Innula racemosa, Ligusticum chiangxiong, Ligusticum lucidum,Mallotus philippinensis, Melicope hayesii, Mimusops elengi, Morindacitrifolia, Moringa oleifera, Naringi crenulata, Nerium indicum,Portulaca oleracea, Portulaca sativa, Psoralea corylifolia, Sapindusrarak, Sesbania grandaflora, Stenoloma chusana, Tiliacora triandra,Terminalia bellerica, tomato glycolipid, and mixtures thereof.

The composition may comprise additional active ingredients havinganti-aging benefits, as it is contemplated that synergistic improvementsmay be obtained with such combinations. Exemplary anti-aging componentsinclude, without limitation, botanicals (e.g., Butea Frondosa extract);thiodipropionic acid (TDPA) and esters thereof; retinoids (e.g.,all-trans retinoic acid, 9-cis retinoic acid, phytanic acid and others);hydroxy acids (including alpha-hydroxyacids and beta-hydroxyacids),salicylic acid and salicylates; exfoliating agents (e.g., glycolic acid,3,6,9-trioxaundecanedioic acid, etc.), estrogen synthetase stimulatingcompounds (e.g., caffeine and derivatives); compounds capable ofinhibiting 5 alpha-reductase activity (e.g., linolenic acid, linoleicacid, finasteride, and mixtures thereof); barrier function enhancingagents (e.g., ceramides, glycerides, cholesterol and its esters,alpha-hydroxy and omega-hydroxy fatty acids and esters thereof, etc.);collagenase inhibitors; and elastase inhibitors; to name a few.

Exemplary retinoids include, without limitation, retinoic acid (e.g.,all-trans or 13-cis) and derivatives thereof, retinol (Vitamin A) andesters thereof, such as retinol palmitatc, retinol acetate and retinolpropionate, and salts thereof.

In another embodiment, the topical compositions of the present inventionmay also include one or more of the following: a skin penetrationenhancer, an emollient, a skin plumper, an optical diffuser, asunscreen, an exfoliating agent, and an antioxidant.

An emollient provides the functional benefits of enhancing skinsmoothness and reducing the appearance of fine lines and coarsewrinkles. Examples include isopropyl myristate, petrolatum, isopropyllanolate, silicones (e.g., methicone, dimethicone), oils, mineral oils,fatty acid esters, or any mixtures thereof. The emollient may bepreferably present from about 0.1 wt % to about 50 wt % of the totalweight of the composition.

A skin plumper serves as a collagen enhancer to the skin. An example ofa suitable, and preferred, skin plumper is palmitoyl oligopeptide. Otherskin plumpers are collagen and/or other glycosaminoglycan (GAG)enhancing agents. When present, the skin plumper may comprise from about0.1 wt % to about 20 wt % of the total weight of the composition.

An optical diffuser is a particle that changes the surface optometricsof skin, resulting in a visual blurring and softening of, for example,lines and wrinkles. Examples of optical diffusers that can be used inthe present invention include, but are not limited to, boron nitride,mica, nylon, polymethylmethacrylate (PMMA), polyurethane powder,sericite, silica, silicone powder, talc, Teflon, titanium dioxide, zincoxide, or any mixtures thereof. When present, the optical diffuser maybe present from about 0.01 wt % to about 20 wt % of the total weight ofthe composition.

A sunscreen for protecting the skin from damaging ultraviolet rays mayalso be included. Preferred sunscreens are those with a broad range ofUVB and UVA protection, such as octocrylene, avobenzone (Parsol 1789),octyl methoxycinnamate, octyl salicylate, oxybenzone, homosylate,benzophenone, camphor derivatives, zinc oxide, and titanium dioxide.When present, the sunscreen may comprise from about 0.01 wt % to about70 wt % of the composition.

Suitable exfoliating agents include, for example, alpha-hydroxyacids,beta-hydroxyacids, oxaacids, oxadiacids, and their derivatives such asesters, anhydrides and salts thereof. Suitable hydroxy acids include,for example, glycolic acid, lactic acid, malic acid, tartaric acid,citric acid, 2-hydroxyalkanoic acid, mandclic acid, salicylic acid andderivatives thereof. A preferred exfoliating agent is glycolic acid.When present, the exfoliating agent may comprise from about 0.1 wt % toabout 80 wt % of the composition.

An antioxidant functions, among other things, to scavenge free radicalsfrom skin to protect the skin from environmental aggressors. Examples ofantioxidants that may be used in the present compositions includecompounds having phenolic hydroxy functions, such as ascorbic acid andits derivatives/esters; beta-carotene; catechins; curcumin; ferulic acidderivatives (e.g. ethyl ferulate, sodium ferulate); gallic acidderivatives (e.g., propyl gallate); lycopene; reductic acid; rosmarinicacid; tannic acid; tetrahydrocurcumin; tocopherol and its derivatives;uric acid; or any mixtures thereof. Other suitable antioxidants arethose that have one or more thiol functions (—SH), in either reduced ornon-reduced form, such as glutathione, lipoic acid, thioglycolic acid,and other sulfhydryl compounds. The antioxidant may be inorganic, suchas bisulfites, metabisulfites, sulfites, or other inorganic salts andacids containing sulfur. Compositions of the present invention maycomprise an antioxidant preferably from about 0.001 wt % to about 10 wt%, and more preferably from about 0.01 wt % to about 5 wt %, of thetotal weight of the composition.

Other conventional additives include: vitamins, such as tocopherol andascorbic acid; vitamin derivatives such as ascorbyl monopalmitate;thickeners such as hydroxyalkyl cellulose; gelling agents; structuringagents such as bentonite, smectite, magnesium aluminum silicate andlithium magnesium silicate; metal chelating agents such as EDTA;pigments such as zinc oxide and titanium dioxide; colorants; emollients;and humectants.

It is preferred that the composition be essentially free of componentshaving a strong oxidizing potential, including for example, organic orinorganic peroxides. By “essentially free of” these components is meantthat the amounts present are insufficient to have a measurable impact onthe collagen I, desmogleins, and/or dermatopontin enhancing activity ofthe 1-aroyl-N-(2-oxo-3-piperidinyl)-2-piperazine carboxamides. In someembodiments, this will be, on a molar basis in relation to the amount of1-aroyl-N-(2-oxo-3-piperidinyl)-2-piperazine carboxamide, less than 1%.

In one embodiment, the composition of the invention comprising a1-aroyl-N-(2-oxo-3-piperidinyl)-2-piperazine carboxamide may have a pHbetween about 1 and about 8. In certain embodiments, the pH of thecomposition will be acidic, i.e., less than 7.0., and preferably will bebetween about 2 and about 7, more preferably between about 3.5 and about5.5.

The invention provides a method for treating aging skin by topicallyapplying a composition comprising a1-aroyl-N-(2-oxo-3-piperidinyl)-2-piperazine carboxamide, preferably ina cosmetically acceptable vehicle, over the affected area for a periodof time sufficient to reduce, ameliorate, reverse or preventdermatological signs of aging. This method is particularly useful fortreating signs of skin photoaging and intrinsic aging.

Generally, the improvement in the condition and/or aesthetic appearanceis selected from the group consisting of: reducing dermatological signsof chronological aging, photo-aging, hormonal aging, and/or actinicaging; preventing and/or reducing the appearance of lines and/orwrinkles; reducing the noticeability of facial lines and wrinkles,facial wrinkles on the cheeks, forehead, perpendicular wrinkles betweenthe eyes, horizontal wrinkles above the eyes, and around the mouth,marionette lines, and particularly deep wrinkles or creases; preventing,reducing, and/or diminishing the appearance,and/or depth of lines and/orwrinkles; improving the appearance of suborbital lines and/orperiorbital lines; reducing the appearance of crow's feet; rejuvenatingand/or revitalizing skin, particularly aging skin; reducing skinfragility; preventing and/or reversing of loss of glycosaminoglycansand/or collagen; ameliorating the effects of estrogen imbalance;preventing skin atrophy; preventing, reducing, and/or treatinghyperpigmentation; minimizing skin discoloration; improving skin tone,radiance, clarity and/or tautness; preventing, reducing, and/orameliorating skin sagging; improving skin firmness, plumpness,suppleness and/or softness; improving procollagen and/or collagenproduction; improving skin texture and/or promoting retexturization;improving skin barrier repair and/or function; improving the appearanceof skin contours; restoring skin luster and/or brightness; minimizingdermatological signs of fatigue and/or stress; resisting environmentalstress; replenishing ingredients in the skin decreased by aging and/ormenopause; improving communication among skin cells; increasing cellproliferation and/or multiplication; increasing skin cell metabolismdecreased by aging and/or menopause; retarding cellular aging; improvingskin moisturization; enhancing skin thickness; increasing skinelasticity and/or resiliency; enhancing exfoliation; improvingmicrocirculation; decreasing and/or preventing cellulite formation; andany combinations thereof.

Without wishing to be bound by any particular theory, it is believedthat the compositions of the present invention enhance and improve theaesthetic appearance of skin by stimulation of collagen and/or byimproving the cell-to-cell adhesion between keratinocytes through thestimulation of Desmogleins.

The composition will typically be applied to the skin one, two, or threetimes daily for as long as is necessary to achieve desired anti-agingresults. The treatment regiment may comprise daily application for atleast one week, at least two weeks, at least four weeks, at least eightweeks, or at least twelve weeks. Chronic treatment regimens are alsocontemplated.

The 1-aroyl-N-(2-oxo-3-piperidinyl)-2-piperazine carboxamide activecomponent is topically applied to an “individual in need thereof,” bywhich is meant an individual that stands to benefits from reducingvisible signs of skin damage or aging. In a specific embodiment, the1-aroyl-N-(2-oxo-3-piperidinyl)-2-piperazine carboxamide component isprovided in a pharmaceutically, physiologically, cosmetically, anddermatologically-acceptable vehicle, diluent, or carrier, where thecomposition is topically applied to an affected area of skin and left toremain on the affected area in an amount effective for improving thecondition and aesthetic appearance of skin.

In one embodiment, methods for treating fine lines and wrinkles comprisetopically applying the inventive1-aroyl-N-(2-oxo-3-piperidinyl)-2-piperazine carboxamide compositions tothe skin of an individual in need thereof, e.g., topically applicationdirectly to the fine line and/or wrinkle in an amount and for a timesufficient to reduce the severity of the fine lines and/or wrinkles orto prevent or inhibit the formation of new fine lines and/or wrinkles.The effect of a composition on the formation or appearance of fine linesand wrinkles can be evaluated qualitatively, e.g., by visual inspection,or quantitatively, e.g., by microscopic or computer assistedmeasurements of wrinkle morphology (e.g., the number, depth, length,area, volume and/or width of wrinkles per unit area of skin). Thisembodiment includes treatment of wrinkles on the skin of the hands,arms, legs, neck, chest, and face, including the forehead,

It is also contemplated that the compositions of the invention will beuseful for treating thin skin by topically applying the composition tothin skin of an individual in need thereof. “Thin skin” is intended toinclude skin that is thinned due to chronological aging, menopause, orphoto-damage. In some embodiments, the treatment is for thin skin inmen, whereas other embodiments treat thin skin in women, pre-menopausalor post-menopausal, as it is believed that skin thins differently withage in men and women, and in particular in women at different stages oflife.

The method of the invention may be employed prophylactically toforestall aging including in patients that have not manifested signs ofskin aging, most commonly in individuals under 25 years of age. Themethod may also reverse or treat signs of aging once manifested as iscommon in patients over 25 years of age.

EXAMPLES 1. Example 1 Stimulation of Collagen 1

Human dermal fibroblasts (Cascade Biologics) were cultured in 96-welltissue culture plates in growth medium (DMEM, 5% FBS, 1% L-Glut, and 1%antibiotics) and incubated for 24 hours at 37° C. Cells were thentreated with test active diluted in growth medium and incubated for 48hours at 37° C., after which the culture media was collected and assayedfor the presence of procollagen 1. Procollagen 1 levels were assayedusing an ELISA kit from Takara (Procollagen Type-1 C-Peptide EIA Kit,Takara Bio Inc.) as per manufacturer's instructions. Fibroblasts treatedwith 5 μg/ml of 1-aroyl-N-(2-oxo-3-piperidinyl)-2-piperazine carboxamideshowed a 75.4% increase in collagen synthesis compared to control.

2. Example 2 Stimulation of Desmogleins

Normal human keratinocytes were cultured in 96 well tissue culturetreated plates in Epilife medium with growth supplements (CascadeBiologics Inc.). Cells were treated with test material or adimethylsulfoxide vehicle control diluted in growth medium for 24 hoursin a humidified 37° C. incubator with 10% CO2. After incubation, growthmedium from each plate was removed and 100 μl of lysis buffer was addedto each of the wells and placed in the humidified 37° C. incubator with10% CO₂ for 30 minutes. At the end of the incubation period, the cellswere collected in freezer plates and placed in a −80° C. freezer, untilanalysis. Changes in mRNA for Desmoglein 3 (DSG3) after treatment wereanalysed using Panomics Quantigene multiplex assay that employs branchedDNA technology. The increase (%) in mRNA for each endpoint wascalculated by comparing the test results of the extract to the control.

Keratinocytes treated with 1-aroyl-N-(2-oxo-3-piperidinyl)-2-piperazinecarboxamide at a concentration of 0.0005% showed a 95% increase inDesmoglein 1 expression after 24 hours. The effect observed was anaverage of three samples assayed and was statistically significant atp<0.05. Treatment with 0.00005% of the test material did not show astatistically significant increase in Desmoglein 1 expression.

3. Example 3 Stimulation of Dermatopontin Production

Normal human dermal fibroblasts were cultured in 96 well tissue culturetreated plates, containing appropriate culture medium. Cells weretreated with 1-aroyl-N-(2-oxo-3-piperidinyl)-2-piperazine carboxamidetest material, diluted in growth medium, for 24 hours in a humidified37° C. incubator with 10% CO₂. After incubation, growth medium from eachplate was removed and 100 μl of lysis buffer was added to the wells andplaced in 37° C. incubator with10% CO₂ for 30 minutes. At the end ofincubation, the cells were collected in freezer plates and placed in−80° C. freezer, until analysis. Changes in mRNA for Dermatopontin aftertreatment were analysed using Panomics Quantigene multiplex assay thatemploys a branched DNA technology. Percent increase in mRNA for MT2A wascalculated by comparing the test results to that of the vehicle control.Fibroblasts treated with 0.0005% or 0.00005% of1-aroyl-N-(2-oxo-3-piperidinyl)-2-piperazine carboxamide showed a 62%and 43% stimulation in mRNA levels for Dermatopontin respectively. Allresults reported are statistically significant at p<0.05.

4. Example 4 Representative Formulations

Representative formulations of skin care products comprising effectiveamounts of 1-aroyl-N-(2-oxo-3-piperidinyl)-2-piperazine carboxamideactive agent are provided in Table 1.

TABLE 1 Concentration (wt. %) Formula Formula Formula FormulaDescription Purpose 1 2 3 4 Deionized water diluent qs qs qs qs 100%100% 100% 100% Acrylates/C10-30 emulsifier 1 1 1 1 Alkyl AcrylateCrosspolymer Cetyl Ethylhexanoate emollient 10 10 10 10 C12-15 Alkylemollient 3.9 3.9 3.9 3.9 Benzoate Isopropyl Isostearate emollient 3 3 33 Diisopropyl dimer emollient 0.1 0.1 0.1 0.1 dillinoleate Tocopherylacetate anti- 0.5 0.5 0.5 0.5 oxidant Butylene glycol humectant 2 2 2 2Propylene glycol humectant 1 1 1 1 Dimethicone PEG-7 co- 0.5 0.5 0.5 0.5isostearate emulsifier Methyl gluceth-20 humectant 0.5 0.5 0.5 0.5Triethanolamine neutralizer 1 1 1 1 Acrylates/acrylamide emulsifier 1.51.5 1.5 1.5 copolymer/mineral oil DMDM Hydantoin/ preser- 0.4 0.4 0.40.4 Iodopropynyl- vative butylcarbonate 1-aroyl-N-(2-oxo-3- active 0.30.03 0.01 0.005 piperidinyl)-2- piperazine carboxamide

Formulas 1-4 are topically applied to skin, including skin of the face,to prevent, treat, and/or reduce signs of photo-aging and/or intrinsicaging, such as fine lines and wrinkles. The formulas are topicallyapplied to the skin for an amount of time sufficient to provide aclinically measurable reduction in one or more signs of skin aging,which typically entails once, twice, or three-times daily treatment forone, two, or three weeks up to about eight weeks or more, includingchronic treatment.

5. Example 5 Synthesis of Representative Compound

The synthesis of a representative1-aroyl-N-(2-oxo-3-piperidinyl)-2-piperazine carboxamide from pyrazine2-carboxylic acid following is shown in the scheme below.

Synthesis of Compound 1

To pre-cooled methanol (24900 mL, 3 Vol) was added NaOMe (3683 g, 68.2mol. 1.8 equiv) at −5 to 0° C. (temperature rose from −5 to 25° C.). Tothis a solution of L-ornithine methyl ester hydrochloride (8300 g) inmethanol (41500 mL, 5 Vol) was added maintaining the temperature below0° C. The reaction mixture was stirred for 2 h and the monitored by ¹HNMR. After completion of the reaction, as indicated by ¹H NMR, MTBE(50000 mL, 6 Vol) was added to the reaction mixture maintainingtemperature below 0° C. The slurry was stirred for 30 min and filteredthrough celite bed and washed with 50% MTBE in MeOH (2×2000 mL). Thefiltrate was concentrated under high vacuum (1 mm), keeping the bathtemperature at 30-35° C. to afford a solid mass that was azeotroped withTHF (2×2000 mL). The desired product came out as pale yellow solids(4320 g, 100%) and the final product was characterized by ¹H NMR, whichwas consistent with no major impurities.

Synthesis of Compound 5

To a 5-L, 3-neck RB-flask was added methanol (1800 mL) at RT. Compound 2(300 g, 1.369 mol, 1.0 equiv) was charged at RT. The reaction mixturewas cooled to −2° C. and added 25 wt % NaOMe solution in methanol (532.3mL, 2.46 mol, 1.8 equiv) by maintaining the temperature at −5 to −2° C.(addition time 1 h). The reaction mixture was stirred for 2 h at −5 to−2° C. and monitored by ¹H NMR. MTBE (1800 mL, 6 vol) was addedmaintaining the temperature at 5-10° C. and stirred for 30 min. Theslurry was filtered over celite bed (filtration was slow and took 1 h).Total volume of the filtrate was 3600 mL, which was concentrated to 300mL under reduced pressure (rotovap, bath temp 30° C.). This solutioncontaining compound 3 was carried to the salt formation reaction.

To a 5-L, 3-neck RB-flask was added N-methyl-2-pyrolidinone (NMP, 1200mL, 7 vol) at RT. Compound 4 (169.86 g, 1.369 mol, 1 equiv) was chargedat RT. Compound 4 was partially soluble at RT and thus heated to 40-45°C. to get a clear solution. The solution containing compound 3 (volume300 mL) at 30° C. over 15 min and an exotherm was observed (from 30° C.to 44° C.). The slurry was stirred for 3 h at RT and MTBE (2000 mL) wasadded. The reaction mixture was cooled to 5-10° C. over 30 min andfiltered. The solids were slurried in MTBE (2000 mL) and stirred for 15min at RT. The slurry was filtered and dried under vacuum to affordcompound 7 as a white solid (240 g, 86%). ¹H NMR of the isolated saltshowed 58:42 ratio of amine (3) and acid (4).

Synthesis of Compound 6

A 100-L jacketed reactor was charged with 1-methyl-2-pyrrolidinone (22L) at RT. Compound 5 (2.7 Kg, 11.34 mol, l equiv) was charged then addedHOBt (345 g, 2.25 mol, 0.2 eq) followed by EDC.HCl (2.7 Kg, 14.0 mol,1.25 equiv) portion wise maintaining the temperature at RT (someexotherm was observed, temperature rose from 25° C. to 30° C.). Thereaction mixture was stirred at RT for 24 h and monitored by HPLC andELSD. No starting materials were observed. MeOH (5.4 L) followed by MTBE(21 L) were added at RT and stirred for 30 min maintaining thetemperature at 5-10° C. The solids were filtered and washed with MTBE(12 L). The product was dried in vacuum oven.

Synthesis of Compound 7

N-(2-Oxopiperidin-3-yl) pyrazine-2-carboxamide (6) (2.6 Kg, 99% pure byHPLC) and Pd(OH)₂ (520 g) were charged to a 50-L reactor and ethanol (39L, 15 vol) was added. The mixture was purged with nitrogen twice andallowed to stir at 70° C. under hydrogen atmosphere (80 psi) for 12 h.TLC (50:50 MeOH/Ethyl acetate) analysis showed formation of product (nostarting material). The reaction mixture was cooled to RT and filteredthrough a celite bed. The celite bed was washed with of EtOH/CH₂Cl₂(50:50) (2×19.5 L). Solvent was evaporated under reduced pressure.Product was obtained as a thick liquid. To this was added methylenechloride (10 vol) and swapped the residual ethanol under reducedpressure at 45° C. Methylene chloride (2×5 vol) was added and swappedthe residual solvent under reduced pressure at 45° C. The product wasobtained as off-white solids (2.85 kg). ¹H NMR was consistent and showed4% ethanol and 94% pure by ELSD. The product can then be dried.

Synthesis of Compound 8

Synthesis of compound 8 was performed on 350.0 g (7) scale.

TABLE 2 Scale Entry (7) Conditions Yield Comments 1 350 g 7 (1.548 mol),Boc 260 g Confirmed by ¹H anhydride (0.9 equiv), (51.5%)¹ NMR and ELSD.MeOH: CH₂Cl₂ [1:19, total 20 vol], ¹not isolated; yield was determinedfrom LOD of an aliquot

To a solution of compound 7 (350 g, 1.0 equiv) in methanol (1.0 vol) andmethylene chloride (14 vol) was added a solution of (Boc)₂O (0.9 equiv)in CH₂Cl₂ (5 vol) drop wise over 6 h at 0-5° C. The reaction progresswas monitored by TLC and ELSD. After completion of the addition nostarting material was observed. To the reaction mixture was added brinesolution (400 mL, 5 vol) and stirred for 15 minutes then separated theaqueous layer and extracted with methylene chloride (3×500 mL). 15%Citric acid solution (7 vol) was added and stirred for 15 minutes. Theaqueous layer was separated and basified with 3 N NaOH solution (5 vol)then extracted with methylene chloride (30 vol). The organic phase waswashed with brine (750 mL), concentrated approximately to 10 vol and thesolution (KF 0.1%) was taken into the next step. The yield of 8 wasdetermined to be 51.5% based on LOD analysis of little aliquot. Mono Bocprotection can also be optimized in water.

Synthesis of Compound 9

TABLE 3 Scale Entry (8) Conditions Yield Comments 1 260 g¹ 8 (1.0 equiv,solution 366 g (assumed HPLC purity: from previous step), 4- to be 91%(AUC) by methoxybenzol chloride quantitative) HPLC (1.0 equiv), Et₃N(2.0equiv), CH₂Cl₂(10 vol) ¹not isolated; taken solution from previous stepinto this step; yield was determined from LOD of an aliquot.

To a solution of compound 8 in methylene chloride was added Et₃N (2.0equiv) and the mixture was stirred at 0-5° C. for 10 minutes then added4-methoxybenzoyl chloride (p-anisoyl chloride) drop-wise over 30 min.The reaction progress was monitored by TLC and after 1 h no startingmaterial was observed. To the reaction mixture was added 15% citric acidsolution (5 vol) and separated organic layer washed with 1 N NaOHsolution (5 vol). The organic phase was washed with brine andconcentrated to approximately 2 vol and then added 5 vol of IPAc. Thesolution was concentrated again to approximately 2 vol (a sample wassubmitted for OVI analysis). Finally the clear solution (submitted forKF analysis) was diluted with 3 vols of IPAc (total 5 vol, 1.75 L) andtaken into the next step. The yield of the solution was assumed to bequantitative.

Synthesis of Compound 10

TABLE 4 Scale Entry (9) Conditions Yield Comments 1 366 g¹ 9 (1.0 equiv,solution in 510 g² Isolated as HCl salt IPAc from previous (~90%, 93%(can be handled step), 5 M HCl in (AUC) by isolation under dioxane (2.5equiv) HPLC) nitrogen) ¹Crude yield from previous step was determinedfrom LOD of solution from Boc protection step. ²Contains 40% of IPAc;drying is in progess. The purity may be upgraded using hot EtOAc slurry.

To a solution of compound 9 from the previous step was added 5 M HCl indioxane (2.5 equiv) slowly at 10° C. and the slurry stirred at roomtemperature for 14 h. The reaction progress was monitored by TLC andHPLC, and it showed 11% starting material by HPLC (the reaction mixturewas a slurry and analysis may not be accurate). The mixture was dilutedwith 2 vol of IPAc and stirred for 1 h. The solids were filtered, washedwith IPAc. Wet wt: 515 g (contains 40% IPAc by NMR analysis). Yield: 50%over 3 steps (Boc protection, benzoylation and deprotection).

Synthesis of 11 (a 1-aroyl-N-(2-oxo-3-piperidinyl)-2-piperazinecarboxamide)

Synthesis of a representative1-aroyl-N-(2-oxo-3-piperidinyl)-2-piperazine carboxamide was performedon 45.0 g scale

TABLE 5 Entry Scale Conditions Yield Comments 1 45.0 g 10, MsCl (1.1equiv), Et₃N 40.0 g Confirmed by (2.0 equiv), CH₂Cl₂ (10 (73%) ¹H NMRand vol), rt HPLC (95%)

To a solution of compound 10 (45.0 g freebase, 0.125 mol, 1.0 equiv) indichloromethane (10 vol) was added triethylamine (25.4 g, 0.25 mol, 2.0equiv) and stirred the reaction mixture at 0-5° C. for 10 minutes, thenmesylchloride (1.1 equiv) added drop wise. After completion of theaddition, the reaction mixture was stirred for 1 h (reaction progresswas monitored by TLC and HPLC). The reaction was deemed to be completedwhen <2% starting material remained. The reaction mixture was quenchedwith saturated bicarbonate solution (225 mL, 5 vol) and diluted with 200mL of dichloromethane. The organic phase was separated, washed with 1 NHCl, dried and concentrated to give compound 11 (a1-aroyl-N-(2-oxo-3-piperidinyl)-2-piperazine carboxamide) (40.0 g, 73%)as an off-white solid. NMR was consistent and 95.5% purity wasdetermined by HPLC. An HCl salt of compound 10 may be used in a scale upreaction.

All references including patent applications and publications citedherein are incorporated herein by reference in their entirety and forall purposes to the same extent as if each individual publication orpatent or patent application was specifically and individually indicatedto be incorporated by reference in its entirety for all purposes. Manymodifications and variations of this invention can be made withoutdeparting from its spirit and scope, as will be apparent to thoseskilled in the art. The specific embodiments described herein areoffered by way of example only, and the invention is to be limited onlyby the terms of the appended claims, along with the full scope ofequivalents to which such claims are entitled.

1. A method for providing a benefit to human skin comprising topicallyapplying to the skin of an individual in need thereof an effectiveamount of a 1-aroyl-N-(2-oxo-3-piperidinyl)-2-piperazine carboxamidecompound or a diastereomer or cosmetically acceptable salt thereof in acosmetically acceptable vehicle, wherein said1-aroyl-N-(2-oxo-3-piperidinyl)-2-piperazine carboxamide compound, ordiastereomer or cosmetically acceptable salt thereof, has the structureof formula (Ia):

where R₃ and R₆ are independently hydrogen or a group —R₉-R₁₀; R₉represents, independently at each occurrence, a bond; an aliphaticC₁-C₂₀ hydrocarbon radical; a C₁-C₂₀ aromatic hydrocarbon radical; or aC₁-C₂₀ heteroaryl radical; R₁₀ is selected independently at eachoccurrence from hydrogen; —F; —Cl; —Br; —I; —OH;—OR; —NH₂; —NHR; —N(R)₂;—N(R)₃ ⁺; —N(R)—OH; —N(→O)(R)₂; —O—N(R)₂; —N(R)—O—R; —N(R)—N(R)₂;—C═N—R; —N═C(R)₂; —C═N—N(R)₂; —C(═NR)—N(R)₂; —SH; —SR; —CN; —NC; —CHO;—CO₂H; —CO₂ ⁻; —CO₂R; —(C═O)—S—R; —O—(C═O)—H; —O—(C═O)—R; —S—(C═O)—R;—(C═O)—NH₂; —(C═O)—N(R)₂; —(C═O)—NHNH₂; —O—(C═O)—NHNH₂; —(C═S)—NH₂;—(C═S)—N(R)₂; —N(R)—CHO; —N(R)—(C═O)—R; —(C═NR)—O—R; —O—(C═NR)—R; —SCN;—NCS; —NSO; —SSR; —N(R)—C(═O)—N(R)₂; —N(R)—C(═S)—N(R)₂; —SO₂—R;—O—S(═O)₂—R; —S(═O)₂—OR; —N(R)—SO₂—R; —SO₂—N(R)₂; —O—SO₃ ⁻;—O—S(═O)₂—OR; —O—S(═O)—OR; —O—S(═O)—R; —S(═O)—OR; —S(═O)—R; —NO; —NO₂;—NO₃; —O—NO; —O—NO₂; —N₃; —N₂; —N(C₂H₄); —Si(—R)₃; —CF₃; —O—CF₃;—(C═O)—R; —PR₂; —O—P(═O)(OR)₂; —P(═O)(OR)₂; ═O; ═S; ═NR; an aliphaticC₁-C₂₀ hydrocarbon radical; a C₁-C₂₀ aromatic hydrocarbon radical; or aC₁-C₂₀ heteroaryl radical; where R is independently at each occurrencehydrogen or a saturated, partially saturated, or aromatic C₁-C₂₀hydrocarbon radical or halogenated derivative thereof.
 2. The methodaccording to claim 1, where R₃ represents a group —OR.
 3. The methodaccording to claim 2, where R₃ represents —OCH₃.
 4. The method accordingto claim 1, where R₆ is a group —(C═O )—R, where R is selected from thegroup consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, phenyl,toluyl, or benzyl.
 5. The method according to claim 4, where R₆ is agroup —(C═O)—(C₆H₅).
 6. The method according to claim 1, where R₆ is agroup —SO₂—R, where R is selected from the group consisting of methyl,ethyl, propyl, butyl, pentyl, hexyl, phenyl, toluyl, or benzyl.
 7. Themethod according to claim 6, where R₆ is a group —SO₂—CH₃.
 8. The methodaccording to claim 1, wherein said skin benefit is selected from thegroup consisting of: (a) treatment and/or reduction of fine lines orwrinkles, and/or reduction of severity of existing fine lines orwrinkles and/or inhibition of formation of new fine lines or wrinkles,(b) reduction of skin pore size, (c) improvement in skin thickness,plumpness, and/or tautness; (d) improvement in skin suppleness and/orsoftness; (e) improvement in skin tone, radiance, and/or clarity; (f)improvement in procollagen and/or collagen production; (g) improvementin maintenance and remodeling of elastin; (h) improvement in skintexture and/or promotion of retexturization; (i) improvement in skinbarrier repair and/or function; (j) improvement in appearance of skincontours; (k) restoration of skin luster and/or brightness; (l)replenishment of essential nutrients and/or constituents in the skin;(m) improvement of skin appearance decreased by menopause; (n)improvement in skin moisturization; (o) increase in skin elasticityand/or resiliency; or (p) treatment and/or reduction of skin sagging. 9.The method according to claim 8, wherein said skin benefit is thetreatment and/or reduction of fine lines or wrinkles and/or reduction ofseverity of existing fine lines or wrinkles and/or inhibition offormation of new fine lines or wrinkles.
 10. The method according toclaim 8, wherein said skin benefit is the treatment and/or reduction ofskin sagging.
 11. The method according to claim 1, wherein said1-aroyl-N-(2-oxo-3-piperidinyl)-2-piperazine carboxamide compound hasthe structure:

or a diastereomer or a cosmetically acceptable salt thereof.
 12. Themethod according to claim 1, wherein said1-aroyl-N-(2-oxo-3-piperidinyl)-2-piperazine carboxamide compound hasthe structure:

or a diastereomer or a cosmetically acceptable salt thereof.
 13. Amethod for treating wrinkles and/or fine lines comprising topicallyapplying to said wrinkle and/or fine line on the skin of an individualin need thereof an effective amount of a1-aroyl-N-(2-oxo-3-piperidinyl)-2-piperazine carboxamide compound or adiastereomer or a cosmetically acceptable salt thereof in a cosmeticallyacceptable vehicle for a time sufficient to reduce the severity of saidwrinkles or fine lines.
 14. The method according to claim 1, wherein a(R,R) diastereomer comprises at least 95% by weight of the total weightof said compound having the structure of formula (Ia).
 15. The methodaccording to claim 1, wherein a (R,S) diastereomer comprises at least95% by weight of the total weight of said compound having the structureof formula (Ia).
 16. The method according to claim 1, wherein a (S,R)diastereomer comprises at least 95% by weight of the total weight ofsaid compound having the structure of formula (Ia).
 17. The methodaccording to claim 1, wherein a (S,S) diastereomer comprises at least95% by weight of the total weight of said compound having the structureof formula (Ia).